Normal bone remodeling follows a coupled cyclical sequence comprised of two arms: the stimulation of resorption in response to bone formation and the synthesis of new bone as a result of its degradation. The interplay between local and systemic bone remodeling regulatory pathways involves a complex, overlapping, and multitiered program responsible for balancing the normal remodeling sequence. Redundant regulatory mechanisms help to ensure that minor signalling aberrations are not translated into major remodeling disorders such as those associated with osteoporosis and osteoarthritis. The alliance between endocrine, autocrine, and paracrine signals orchestrates bone remodeling via effects upon an everchanging population of stem cells and cells in various stages of development, maturation, physiology, and senescence. Many researchers are investigating the important role of osteoblasts and marrow stromal cells in the regulation of osteoclast development and action. Conversely, the modulatory action of osteoclasts or related cells upon other cells within the bone microenvironment has not received much attention. This underexplored area of bone biology is therefore the central theme of the ongoing research that we plan to continue as part of the current proposal. The primary objective of these studies will be to test the hypothesis that osteoclasts can continue to identify and characterize osteoclast-derived cytokines that modulate osteoblast development and activity, 2) identify other osteoclast metabolic secretory products that influence bone formation, 3) analyze the hormonal, cytokine, and matrix- dependent modulation of the production of osteoclast-derived osteoblast regulatory factor(s) 4) examine the signal transduction mechanisms involved in osteoclast-derived factor regulation of bone formation; included here is to determine whether such factors target subpopulations of osteoblasts. Highly purified avian osteoclasts, avian and human osteoclasts, avian and human osteoclast-like giant cells, and the human preosteoclastic cell line FLG 29.1 will be used to generated synthetic and matrix-released products on human marrow stromal osteoblast precursors, primary chick and rat osteoblasts, and several osteoblasts cell lines. The regulation of known cytokines produced by osteoclasts that appear to influence bone information will be analyzed and novel factors identified. cDNA(s) clones for novel peptide factor(s) will be isolated from an osteoclast cDNA library. These studies will improve our understanding of the osteoclast to osteoblast communication pathway, and hence, the second essential arm of the coupling program of bone remodeling.